The phenotypic changes which distinguish a tumour cell from its normal counterpart are often the result of one or more changes to the genome of the cell. The genes which are expressed in tumour cells, but not in normal counterparts, can be termed “tumour specific” or “tumour associated” genes. These tumour specific or associated genes can be markers for the tumour phenotype.
The process by which the mammalian immune system recognises and reacts to foreign or alien materials is a complex one. An important facet of the system is the response of cytolytic T lymphocytes (CTLs) or T cells. CTLs recognise and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (“HLA”), or major histocompatibility complex molecules (“MHC” molecules), and other peptides derived from larger molecules from within the cells carrying the HLA/MHC complexes. See, in this regard, Male et al., Advanced Immunology (J. P. Lipincott Company, 1987), especially chapters 6-10, and C. A. Janeway et al. Immuno Biology third ed. (Current Biology Ltd. 1997). The interaction of T cells and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific CTL is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the CTL is present. The mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257:880, 1992; Fremont et al., Science 257:919, 1992; Matsumura et al., Science 257:927, 1992; Latron et al., Science 257: 964, 1992.
The mechanism by which T cells recognise cellular abnormalities has also been implicated in cancer. A number of families of genes which are processed into peptides that are presented as HLA/peptide complexes on the surface of tumour cells, with the result that the cells can be lysed by specific CTLs, have been discovered. These genes are said to code for “tumour rejection antigen precursors” or “TRAP” molecules, and the peptides derived therefrom that complex with HLA are referred to as “tumour rejection antigens” or “TRAs”. Intensive efforts have been made in this field and a wealth of human tumour rejection antigens (both TRAPs and TRAs) which are recognised by T cells have been identified (Van den Eynde, B. J., and P. van der Bruggen, 1997, Curr. Opin. Immunol. 9:684.). Among them, a TRAP encoded by the gene MAGE-1 was initially defined by cultivating blood lymphocytes of patient MZ2 in the presence of a melanoma cell line derived from the same patient. A panel of CTL clones was generated by mixed lymphocyte-tumour cell culture (MLTC) techniques, and one of these clones recognised a nonapeptide TRA derived from the MAGE-1 TRAP, which is presented by HLA-A1 (van der Bruggen, P., C. et al., 1991, Science (Wash. D.C.). 254:1643-1647; Traversari, C., et al., 1992, J. Exp. Med. 176:1453-1457 and WO92/20356). It was found later that MAGE-1 belongs to a family of at least seventeen related genes, namely MAGE-1 to −12 (now named MAGE-A1 to -A12)(De Plaen, E., et al., 1994, Immunogenetics. 40:360-369.), MAGE-B1 to -B4 (Muscatelli, F., et al., 1995, Proc. Natl. Acad. Sci. USA. 92:4987-4991; Dabovic, B., et al., 1995, Mammalian Genome. 6:571-580; and Lurquin, C., et al., 1997, Genomics. 46:397-408), and MAGE-C1 (Lucas, S., et al., 1998, Cancer Res. 58:743-752).
Genes of this family are expressed in various tumours of different histological types, but are completely silent in normal tissues with the exception of testis and placenta (De Plaen, E., et al., 1994, Immunogenetics. 40:360-369; Dabovic, B., et al., 1995, Mammalian Genome. 6:571-580; Lurquin, C., et al., 1997, Genomics. 46:397-408; and Lucas, S., et al., 1998, Cancer Res. 58:743-752.). However, as testicular germ cells and placental trophoblasts do not express MHC class 1 molecules (Haas, G. G. Jr., et al., 1988, Am. J. Reprod. Immunol. Microbiol. 18:47-51.), gene expression in these tissues should not lead to antigen expression. Indeed, immunisation of male mice with an antigen encoded by mouse P1A gene, which has the same expression pattern as human MAGE gene, i.e., expressed in tumours, testis and placenta, but silent in other normal tissues, produced strong P1A-specific CTL responses that did not cause testis inflammation or alteration of fertility (Uyttenhove, C., C. et al., 1997, Int. J. Cancer. 70:349-356.). Antigens encoded by MAGE genes are, therefore, suitable candidates for vaccine-based immunotherapy of cancers and as markers for providing a means of identifying a cell as a so treatable tumour cell.